AEGiS-WSJ: The Genetic Front Lines: At the Salk Institute, the promise of gene therapy has never seemed brighter. But the risks have never been more obvious.

Important note: Information in this article was accurate in 2003. The state of the art may have changed since the publication date.

The Genetic Front Lines: At the Salk Institute, the promise of gene therapy has never seemed brighter. But the risks have never been more obvious.

Wall Street Journal - December 9, 2003
Bernard Wysocki Jr., Staff Reporter of The Wall Street Journal

LA JOLLA, Calif. -- More than a decade has passed since scientists began a form of genetic engineering known as gene therapy, injecting genes into living organisms as reinforcements in the body's battle against a variety of serious diseases.

From the start, the technique seemed full of both promise and pitfalls. And these days, that tension is probably greater than ever before, because the scientific advances are looking so promising, while the risks have become all too obvious.

Perhaps no group of people understands the tensions better than the 70 scientists and staffers here at the genetics laboratory of the Salk Institute for Biological Studies, a 43-year-old private research institute perched on a cliff overlooking the Pacific Ocean.

On the one hand, the scientific breakthroughs are coming fast and furious. Just four months ago, for instance, a team here announced a potential gene therapy for Lou Gehrig's disease, in which a gene for a growth hormone was packaged inside a virus and injected into mice. The gene was designed to instruct failing motor nerve cells not to die, and it produced stunning results, greatly prolonging the lives of the experimental mice. Here at Salk, as elsewhere, many more inventive therapies are in the pipeline, with some of the most promising treatments targeting Alzheimer's, Parkinson's, Huntington's and other illnesses in which the main pathology is the death of neurons or nerve cells in the brain and central nervous system.

Casting a Pall

But while Salk and other research centers have been achieving these breakthroughs, at least one death and other serious calamities in gene-therapy trials -- none of them at Salk, which doesn't conduct experiments with people -- have cast a pall over gene-therapy research around the world. The troubles have reverberated here at Salk, which was founded by Jonas Salk, of polio-vaccine fame, in 1960 and has been a pioneer ever since in basic biological research.

The death of an 18-year-old patient, Jesse Gelsinger, came in 1999, during a clinical trial at the University of Pennsylvania. The injection of a gene, via a virus, into Mr. Gelsinger's liver to treat a rare liver ailment triggered an immune response that resulted in multiple organ failure similar to toxic-shock syndrome. Then last year in France, two of eight patients being treated for severe immunodeficiency syndrome developed leukemia. In the wake of that, the Food and Drug Administration curtailed a portion of the gene-therapy trials being conducted in the U.S.

Donald Kohn, a pediatrician at Children's Hospital in Los Angeles and president of the American Society of Gene Therapy, says that after the Jesse Gelsinger death, "the FDA said you have to come to a higher standard" in conducting clinical trials, including much greater documentation of all aspects of the trials. The new obstacles, Dr. Kohn says, have been a deterrent to conducting these trials in academia.

Dr. Kohn adds that while the promise of gene therapy remains great, the leukemia cases in France serve as a reminder that "there are a lot of biological issues we don't know about." As a result, he says, "bridging that gap" between running experiments in mice and running trials in humans is "challenging, and not as easy as we thought 10 years ago."

Here at Salk, senior scientists who for years have pioneered the techniques don't minimize the risks of injecting viruses, as gene-delivery mechanisms, into the body. "The body knows these guys are not good guys," says Inder Verma, a professor at Salk. "They are foreign, so the body immediately mounts an immune response against them. That's why this child Jesse Gelsinger died."

The immune response is just one potential problem with gene therapy. Dr. Verma ticks off others: A gene designed to rid the body of one disease could lodge in the wrong place and cause diabetes, for example. Or the injected material could somehow trigger unprecedented growth in the form of tumors, including cancerous ones.

The paradox of gene therapy is that some of the most potent viruses can be the most powerful forces for good, if properly harnessed. Dr. Verma has spent years developing one of the most powerful of these viral "vectors." It is a disabled form of the HIV virus, which ordinarily consists of nine genes. In the lab, scientists remove six of the genes responsible for the virulent infection associated with AIDS. Then, scientists further manipulate the "envelope" gene so that it attaches to cells in the right manner. Though disabled, this form of the HIV virus nevertheless remains an expert at breaking into cells, almost like a house burglar with special tools for door locks. For the gene therapist, this talent for breaking and entering is good, because the virus can then deliver its payload -- the new gene -- inside the cell. Moreover, while some viruses can enter only cells that are dividing, the HIV virus can enter nondividing cells, such as those in the mature human brain.

Earlier this year, Salk scientists used the disabled HIV virus in research on mice that had been bred with a human gene for Alzheimer's. Once the mice developed large plaques of beta amyloid, the telltale sign of degeneration in Alzheimer's patients, the Salk scientists zapped a memory center of their brains with the disabled HIV virus -- at first without any gene payload, in effect a trial run. On the computer screens used to interpret chemical changes in the brain, the brains of autopsied mice showed a fluorescent green, indicating that the virus had infected the memory center.

Next, Robert Marr, a Salk postdoctoral fellow, packaged into the virus a gene for the enzyme neprilysin, believed to attack and reduce the plaques. Once again, the experiment worked -- with a stunning 49% reduction in plaques in the treated mice, based on autopsies.

These days, Dr. Marr is working with the nearby University of California at San Diego to give similarly impaired mice a battery of cognitive tests, to see whether these "Alzheimer's victims" have better memories if they get injected with the neprilysin-carrying virus. In one test, the mice -- which, like all mice, dislike water -- first swim around in a tub, searching for a small platform just below the surface. Then, to test their memories, the platform is withdrawn, but the mice still try to find the spot where the platform used to be. Letters or pictures on the walls around the basin provide visual cues, and a camera records the mice's every movement, plotting the course they follow as mathematical figures. The treated mice are supposed to find the spot where the platform used to be much faster than the untreated mice. So far, Dr. Marr says, the results look promising.

"The Alzheimer's field is a pretty bright one for new therapies," says Dr. Marr.

Pace of Progress

It's a long ways from testing mice to testing humans. And with even the most promising science running up against the prevailing caution at the FDA and within the research world itself, it will probably be several years before human clinical trials of neprilysin begin. But, reflecting how far the basic science has come, that's a much shorter time frame than in the early days of gene therapy. In the case of one very small clinical trial, involving a human growth factor in the brain of elderly Alzheimer's patients, it took 12 years -- from 1989 until 2001 -- to move from the first published paper on the topic, by Salk faculty member Fred Gage, to the first experiments in a few people.

The gene-therapy program for Lou Gehrig's disease, formally known as amyotrophic lateral sclerosis, or ALS, is also showing promise. The first result of the gene-therapy experiment in mice was announced only in August. But because Salk has partnerships for the research with a number of entities including Johns Hopkins University, Dr. Gage expects that human trials may begin within two years.

This breakthrough began with a remarkable finding by a Salk research fellow, Brian Kaspar. A few years ago, he discovered that a certain virus, called the adeno-associated virus, or AAV, could move in reverse direction -- that is, rather than just traveling from the brain or spinal cord to the motor muscles in the arms and legs, the AAV virus could start at the extremities and move back to the spinal cord.

Dr. Gage recalls brainstorming with Mr. Kaspar, and they hit upon ALS as a disease that might be treated with this reverse-course, or retrograde, virus. If a virus packed with the right gene was injected into the failing muscles of a mouse -- or human -- suffering from ALS, the gene might produce a protein that traveled back to the source of the problem -- and attacked it at the source of the motor failure. The Salk scientists tested several genes, including one that produced a protein called insulin-like growth factor, hoping it would travel back to the spinal cord and slow or even stop the inexorable death of cells at the source.

Slowing the Disease

In one crucial test, Mr. Kaspar and his colleagues injected the muscles of mice, performed autopsies on them and looked for telltale fluorescent coloring to mark the spread of the "good" genes. "The computer lit up green," Mr. Kaspar recalls. "It was a happy day." More important, the drug slowed the progress of the disease. Symptoms appeared later in the treated mice than in the mice without the treatment. The mice had been bred with a particularly virulent strain of ALS, causing them to die within about 120 days of birth if not treated. But the treated mice had far longer life spans, in some cases extending to more than 200 days. The research was funded by Project ALS, the Christopher Reeve Foundation and two institutes within the National Institutes of Health.

Once the results were published in the journal Science in August, Dr. Gage says, the acute tensions over clinical trials began to develop. Some of the problems are merely practical, if mind-numbingly complex: "How many injections? What muscles? What is the dose?" says Dr. Gage, listing the decisions facing the committee formed to prepare for human experiments.

Some advocates argue that because of ALS's deadly nature, the possible risks shouldn't stop a potential therapy from being deployed quickly. On the other hand, Dr. Gage says, given the current worries about gene therapy, he and others are moving very deliberately toward clinical trials, to be conducted by Johns Hopkins.

Here, the mood remains optimistic about the prospect that gene therapy will combat disease. "I think it's going to take a long time," says Mr. Kaspar. "But I have great hope."

Write to Bernard Wysocki Jr. at bernie.wysocki@wsj.com

031209
AP031205

AEGiS is a 501(c)3, not-for-profit, tax-exempt, educational corporation. AEGiS is made possible through unrestricted funding from Boehringer Ingelheim, Bridgestone/Firestone Charitable Trust, Elton John AIDS Foundation UK, the National Library of Medicine, AIDS Walk of Orange County, and donations from users like you.

Always watch for outdated information. This article first appeared in 2003. This material is designed to support, not replace, the relationship that exists between you and your doctor.

AEGiS presents published material, reprinted with permission and neither endorses nor opposes any material. All information contained on this website, including information relating to health conditions, products, and treatments, is for informational purposes only. It is often presented in summary or aggregate form. It is not meant to be a substitute for the advice provided by your own physician or other medical professionals. Always discuss treatment options with a doctor who specializes in treating HIV.

Copyright ©1980, 2003. AEGiS. All materials appearing on AEGiS are protected by copyright as a collective work or compilation under U.S. copyright and other laws and are the property of AEGiS, or the party credited as the provider of the content. .